Compounds and methods for the treatment of malaria

ABSTRACT

as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of malaria.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/042,827, filed on Jul. 23, 2018 (now allowed), which is acontinuation of U.S. patent application Ser. No. 15/035,044, filed onMay 6, 2016, which is the U.S. national phase application, pursuant to35 U.S.C. § 371, of PCT International Application Ser. No.PCT/US14/64962, filed on Nov. 11, 2014, designating the United Statesand published in English, which claims priority to and the benefit ofU.S. Provisional Application No. 61/902,356, filed Nov. 11, 2013; eachof the aforementioned applications are incorporated herein by referencein their entirety.

BACKGROUND OF THE INVENTION

Malaria is a vector-borne infectious disease caused by protozoanparasites and is widespread in tropical and subtropical regions,including parts of the Americas, Asia and Africa. Of the five Plasmodiumparasite species that can infect humans (P. falciparum, P. vivax, P.ovale, P. malariae, and P. knowlesi), the most serious forms of thedisease are caused by P. falciparum and P. vivax. Approximately 515million people are stricken with malaria each year, and between one andthree million of these people die from the disease. The current armamentof approved anti-malarial drugs, such as chloroquine, atovaquone,pyrimethamine, and sulfadoxine, is limited to only a few targets withinthe human malaria parasite, and growing widespread resistance to currentdrugs is prompting the development of new antimalarial agents that havenew biological targets.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula I

wherein the dotted line represents an optional double bond;

m is 0 or 1;

n is 0, 1, or 2;

A is CH or N;

X is absent or —C≡C—;

R¹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Y is C₁-C₆ alkylene, —C(O)NR⁴—; —SO₂—, or —C(O)—;

R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryl C₁-C₆ alkyl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;

R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl;

R⁴ is hydrogen or C₁-C₆ alkyl;

R⁵ and R⁶ are independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ acyl; and

R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉ heterocyclyl;

wherein said compound does not have the structure of any one ofcompounds 1 to 30 of Table 1;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure:

In some embodiments, the compound has the structure:

In certain embodiments, the compound of Formula II has thestereochemistry of Formula IA or IB.

In other embodiments, the compound has the structure:

In certain embodiments, the compound of Formula III, IV, V, or VI hasthe stereochemistry of Formula IA or IB.

In some embodiments, A is CH. In other embodiments, A is N.

In certain embodiments, X is —C≡C—.

In some embodiments, R is C₆-C₁₀ aryl (e.g., phenyl, 2-methoxy-phenyl,4-methoxy-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl,2,4-difluoro-phenyl, or 3,4-difluorophenyl).

In other embodiments, Y is —C(O)NR⁴— (e.g., wherein R⁴ is hydrogen ormethyl).

In certain embodiments, R² is C₆-C₁₀ aryl (e.g., phenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-fluoro-phenyl,3-fluoro-phenyl, or 4-fluoro-phenyl), C₃-C₁₀ carbocyclyl (e.g.,cyclohexyl), or C₂-C₉ heteroaryl (e.g., pyridyl such as 3-pyridyl or4-pyridyl). In some embodiments, R² is 4-substituted phenyl such as4-methoxy-phenyl.

In other embodiments, the compound has the structure:

wherein o and p are independently 1, 2, 3, 4, or 5; and

R⁸ and R⁹ are independently hydrogen, halogen, or C₁-C₆ heteroalkyl.

In certain embodiments, —ZR³ is hydrogen or —CO₂H. In some embodiments,Z is methylene. In other embodiments, R³ is hydroxyl, C₂-C₉ heterocyclyl(e.g., 4-methylpiperazyl, 4-hydroxy-4-methyl-piperidyl,3-hydroxyl-3-methyl-azetidinyl, or morpholinyl), —OCH₂C(O)OH, —NH₂,—NHC(O)CH₃, —NHCH₃, —N(CH₃)₂, or —N(CH₃)C(O)CH₃. In some embodiments, Zis C₁-C₆ heteroalkylene (e.g., —CH₂OCH₂— or —CH₂OCH₂CH₂—). In otherembodiments, R³ is —C(O)R (e.g., wherein R⁷ is hydroxyl, C₁-C₆heteroalkyl such as methoxy, or C₂-C₉ heterocyclyl such as morpholino).

In certain embodiments, the compound of Formula VII has thestereochemistry of Formula IA or IB.

In certain embodiments, —YR² is —CH₂CH₂CF₃.

In some embodiments, Y is methylene or —SO₂—. In other embodiments, R²is 4-methoxy-phenyl.

In certain embodiments, R¹ is C₂-C₉ heteroaryl (e.g., 2-pyridyl or3-pyridyl). In some embodiments, Y is —C(O)NH—. In other embodiments, R²is C₆-C₁₀ aryl (e.g., phenyl, 4-methoxy-phenyl, 2-fluoro-phenyl, or3-fluoro-phenyl). In certain embodiments, —ZR³ is hydrogen, —CH₂OH,—CH₂NH₂, or —CH₂NHC(O)CH₃. In some embodiments, Y is methylene. In otherembodiments, R² is 3-methoxy-phenyl.

In certain embodiments, R¹ is iso-butyl, —CH₂OCH₃, cyclopropyl,cyclopentyl, or cyclohexyl. In some embodiments, Y is —C(O)NH—. In otherembodiments, R² is 2-methoxy-phenyl or 4-methoxy-phenyl. In certainembodiments, Y is —SO₂—. In some embodiments, R² is 4-methoxy-phenyl orbenzyl.

In other embodiments, X is absent.

In certain embodiments, R¹ is hydrogen, C₆-C₁₀ aryl(e.g., phenyl,2-fluoro-phenyl, 3-fluorophenyl, 4-fluoro-phenyl, 3-methyl-phenyl,4-methyl-phenyl), C₃-C₁₀ carbocyclyl (e.g., cyclohexenyl), C₂-C₆heteroaryl (e.g., thiazolyl such as 2-phenyl-1,3-thiazol-4-yl, pyrrolylsuch as 1-phenyl-pyrrol-3-yl, pyridyl such as 4-pyridyl, or pyrazolylsuch as 1-phenyl-H-pyrazol-3-yl).

In some embodiments, —ZR³ is —CH₂OH.

In other embodiments, —YR² is —CH₂CH₂CF₃.

In certain embodiments, Y is —SO₂— and R² is 3-methyl-phenyl or4-fluoro-phenyl.

In some embodiments, Y is —C(O)NH— and R² is 4-methoxy-phenyl.

In another aspect, the invention features a compound selected from anyone of compounds 31 to 95 of Table 1, or a pharmaceutically acceptablesalt thereof.

TABLE 1 Selected Compounds of the Invention LRMS Retention (Calculated:# Structure Name Time Found) 1

((8R,9S,10S)-6-(3- methoxybenzyl)-9-(4- (pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A0.85 C₃₀H₃₄N₃O₂ [M + H]+ 468.26: 468.39 2

(8R,9R,10S)-10- (hydroxymethyl)-N- phenyl-9-(4-(pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.71 C₂₉H₃₁N₄O₂ [M + H]+ 467.24: 467.57 3

(8R,9R,10S)-10- (hydroxymethyl)-N-(2- methoxyphenyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.88 C₃₁H₃₄N₃O₃ [M + H]+ 496.25: 496.58 4

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-(4- (pyridin-2-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.69 C₃₀H₃₂N₄O₃ [M + H]+ 497.25: 497.59 5

((8R,9S,10R)-6-((4- fluorophenyl)sulfonyl)- 9-(2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)- 1,6- diazabicyclo[6.2.0] decan-10-yl)methanolMethod A 0.88 C₂₇H₃₄FN₂ [M + H]+ 485.22: 485.49 6

(8R,9R,10R)-10- (hydroxymethyl)-N- phenyl-9-(4-(pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.70 C₂₉H₃₁N₄O₂ [M − H]− 465.24: 465.27 7

((8S,9S,10R)-9-(3′- methyl-[1,1′-biphenyl]- 4-yl)-6-(m-tolylsulfonyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A0.91 C₂₉H₃₅N₂O₃S [M + H]+ 491.229: 491.50 8

(8S,9S,10S)-N-(3- fluorophenyl)-10- (hydroxymethyl)-9-(4- ((4-methoxyphenyl)ethynyl) phenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.85 C₃₁H₃₃FN₃O₃ [M + H]+ 514.243: 514.449

((8R,9S,10R)-9-(4′- fluoro-[1,1′-biphenyl]- 4-yl)-6-(3,3,3-trifluoropropyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A0.83 C₂₄H₂₉F₄N₂O [M + H]+ 437.214: 437.40 10

(8R,9R,10R)-N-(2- fluorophenyl)-10- (hydroxymethyl)-9-(4- (pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.71 C₂₉H₃₀FN₄O₂ [M + H]+ 485.227: 485.42 11

(8R,9R,10S)-N-(4- fluorophenyl)-10- (hydroxymethyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.84 C₃₀H₃₁FN₃O₂ [M + H]+ 484.23: 484.42 12

(8R,9S,10R)-N-(2- fluorophenyl)-10- hydroxymethyl)-9-(4- (pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.69 C₂₉H₃₀FN₄O₂ [M + H]+ 485.23: 485.46 13

(8R,9R,10S)-N-(3- fluorophenyl)-10- (hydroxymethyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.85 C₃₀H₃₁FN₃O₂ [M + H]+ 484.23: 484.56 14

(8S,9R,10S)-9-(4- (cyclopropylethynyl) phenyl)-10- (hydroxymethyl)-N-(2-methoxyphenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.78 C₂₈H₃₄N₃O₃ [M + 2H]+ 461.25: 461.62 15

((8S,9S,10S)-9-(4-((2- methoxyphenyl)ethynyl) phenyl)-6-(3,3,3-trifluoropropyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A0.84 C₂₇H₃₂F₃N₂O₂ [M + H]+ 473.23: 473.37 16

((8R,9S,10R)-9-(3′- fluoro-[1,1′-biphenyl]- 4-yl)-6-(3,3,3-trifluoropropyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A0.83 C₂₄H₂₉F₄N₂O [M + H]+ 437.21: 437.32 17

((8S,9S,10S)-6-(3- methoxybenzyl)-9-(4- (pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A0.75 C₃₀H₃₄N₃O₂ [M + H]+ 468.26: 468.41 18

(8S,9S,10S)-N-(2- fluorophenyl)-10- (hydroxymethyl)-9-(4- ((4-methoxyphenyl)ethynyl) phenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.83 C₃₁H₃₃FN₃O₃ [M + H]+ 514.24: 514.6019

((8R,9S,10R)-6- (benzylsulfonyl)-9-(4- (4-methylpent-1-yn-1-yl)phenyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A 0.86C₂₈H₃₇N₂O₃S [M + H]+ 481.245: 481.46 20

((8R,9S,10R)-6-((4- methoxyphenyl)sulfonyl)- 9-(4-(3-methoxyprop-1-yn-1- yl)phenyl)-1,6- diazabicyclo[6.2.0]decan-10-yl)methanol Method A 0.73 C₂₆H₃₃N₂O₅S [M + H]+ 485.20: 485.3821

((8S,9R,10S)-9-([1,1′- biphenyl]-4-yl)-6- (3,3,3-trifluoropropyl)- 1,6-diazabicyclo[6.2.0] decan-10-yl)methanol Method A 0.8 C₂₄H₃₀F₃N₂O [M +H]+ 419.22: 419.28 22

(8R,9R,10S)-N-(2- fluorophenyl)-10- (hydroxymethyl)-9-(4- (pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.72 C₂₉H₃₀FN₄O₂ [M + H]+ 485.23: 485.47 23

(8R,9R,10R)-9-(4- (cyclopentylethynyl) phenyl)-10- (hydroxymethyl)-N-(2-methoxyphenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.91 C₃₀H₃₈N₃O₃ [M + H]+ 488.28: 488.42 24

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-(4-(4-methylpent-1-yn-1- yl)phenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.84 C₂₉H₃₈N₃O₃ [M + H]+ 476.28: 476.48 25

(8R,9R,10R)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-(4- (pyridin-2-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.68 C₃₀H₃₃N₄O₃ [M + H]+ 497.25: 497.55 26

((8R,9S,10R)-9-(4′- methyl-[1,1′-biphenyl]- 4-yl)-6-(m-tolylsulfonyl)-1,6- diazabicyclo[6.2.0] decan-10-yl)methanol Method A0.87 C₂₉H₃₅N₂O₃S [M + H]+ 491.23: 491.44 27

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.83 C₃₁H₃₄N₃O₃ [M + H]+ 496.25: 496.48 28

(8R,9R,10R)-N-(3- fluorophenyl)-10- (hydroxymethyl)-9-(4- (pyridin-3-ylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.72 C₂₉H₃₀FN₄O₂ [M + H]+ 485.23: 485.50 29

(8R,9S,10R)-N-(2- fluorophenyl)-10- (hydroxymethyl)-9-(4- ((4-methoxyphenyl)ethynyl) phenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.80 C₃₁H₃₃FN₃O₃ [M + H]+ 514.24: 514.3530

(8R,9R,10S)-10- (hydroxymethyl)-N- phenyl-9-(4- (phenylethynyl)phenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A 0.83 C₃₀H₃₂N₃O₂[M + H]+ 466.24: 466.5 31

(8R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9- phenyl-1,6-diazabicyclo[6.2.0] decane-6-carboxamide Method A 0.67 C₂₃H₃₀N₃O₃ [M +H]+ 396.22: 396.43 32

(8R,9S,10S)-N-(4- methoxyphenyl)-10- [(4-methylpiperazin-1-yl)methyl]-9-[4-(2- phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.59 C₃₆H₄₄N₅O₂ [M + H]+ 578.34: 578.55 33

(8R,9S,10S)-10-[(4- hydroxy-4- methylpiperidin-1- yl)methyl]-N-(4-methoxyphenyl)-9-[4- (2- phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.89 C₃₇H₄₅N₄O₃ [M + H]+ 593.34: 593.57 34

(6R,7R,8S)-8- (hydroxymethyl)-N-(4- methoxyphenyl)-7-[4- (2-phenylethynyl)phenyl]- 1,4- diazabicyclo[4.2.0] octane-4-carboxamideMethod A 0.79 C₂₉H₃₀N₃O₃ [M + H]+ 468.22: 468.46 35

2-{[(8R,9R,10S)-6-[(4- methoxyphenyl) carbamoyl]-9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decan-10-yl]methoxy}acetic acid Method A 0.48 C₃₃H₃₆N₃O₅ [M + H]+ 554.26: 554.1436

[(8R,9R,10S)-6-(4- methoxybenzoyl)-9-[4- (2- phenylethynyl)phenyl]- 1,6-diazabicyclo[6.2.0] decan-10-yl]methanol Method A 0.84 C₃₁H₃₃N₂O₃ [M +H]+ 481.24: 481.45 37

(8R,9S,10S)-10- (aminomethyl)-N-(4- methoxyphenyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.84 C₃₁H₃₅N₄O₂ [M + H]+ 495.27: 495.49 38

(8R,9R,10S)-9-{4-[2- (3- fluorophenyl)ethynyl] phenyl}-10-(hydroxymethyl)-N-(4- methoxyphenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.83 C₃₁H₃₃FN₃O₃ [M + H]+ 514.24: 514.4939

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-[4-(2-phenyl-1,3-thiazol- 4-yl)phenyl]-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.84 C₃₂H₃₅N₄O₃S 554.235: 553.47 40

[(8R,9R,10S)-6-(4- methoxybenzene- sulfonyl)-9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decan-10-yl]methanolMethod A 0.88 C₃₀H₃₃N₂O₄S [M + H]+ 517.21: 517.46 41

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-(4-phenylphenyl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.78 C₂₉H₃₄N₃O₃ [M + H]+ 472.25: 472.49 42

(8R,9R,10S)-9-[4-(4- fluorophenyl)phenyl]- 10-(hydroxymethyl)-N-(4-methoxyphenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamide MethodA 0.78 C₂₉H₃₃FN₃O₃ [M + H]+ 490.243: 490.49 43

(8R,9S)-N-(4- methoxyphenyl)-9-{4- [2-(pyridin-2- yl)ethynyl]phenyl}-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A 0.79 C₂₉H₃₁N₄O₂[M + H]+ 467.237: 467.43 44

(8R,9R,10S)-N- cyclohexyl-10- (hydroxymethyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.88 C₃₀H₃₈N₃O₂ [M + H]+ 472.289: 472.50 45

(8R,9R,10S)-9-[4-(2- cyclohexylethynyl) phenyl]-10-(hydroxymethyl)-N-(4- methoxyphenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.90 C₃₁H₄₀N₃O₃ [M + H]+ 502.299: 502.4946

(8R,9R,10S)-9-[4-(2- fluorophenyl)phenyl]- 10-(hydroxymethyl)-N-(4-methoxyphenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamide MethodA 0.78 C₂₉H₃₃FN₃O₃ [M + H]+ 490.24: 490.49 47

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0]dec- 3-ene-6-carboxamideMethod A 0.80 C₃₁H₃₂N₃O₃ [M + H]+ 494.24: 494.22 48

(8R,9S,10R)-10- (aminomethyl)-N-(4- methoxyphenyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.81 C₃₁H₃₅N₄O₂ [M + H]+ 495.27: 495.21 49

(8R,9R,10S)-N-(2- fluorophenyl)-10- (hydroxymethyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.86 C₃₀H₃₁FN₃O₂ [M + H]+ 484.23: 484.46 50

(8R,9R,10S)-10- (hydroxymethyl)-9-[4- (2- phenylethynyl)phenyl]-N-(pyridin-4-yl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.76 C₂₉H₃₀N₄O₂ [M − H]− 466.237: 465.39 51

(8R,9R,10S)-9-{4-[2- (4- fluorophenyl)ethynyl] phenyl}-10-(hydroxymethyl)-N-(4- methoxyphenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.83 C₃₁H₃₃FN₃O₃ [M + H]+ 514.24: 514.4952

(8R,9R,10R)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.83 C₃₁H₃₃N₃O₃ [M + H]+ 496.25: 496.47 53

(8R,9R,10S)-6-[(4- methoxyphenyl) carbamoyl]-9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-10-carboxylicacid Method A 0.76 C₃₁H₃₂N₃O₄ [M + H]+ 510.231: 510.38 54

(8R,9R,10S)-N-(4- fluorophenyl)-10- (hydroxymethyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.84 C₃₀H₃₀FN₃O₂ [M + H]+ 484.232: 484.42 55

(8R,9S,10S)-N-(4- methoxyphenyl)-10- (morpholin-4- ylmethyl)-9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.90 C₃₅H₄₁N₄O₃ [M + H]+ 565.31: 565.29 56

(8R,9R,10S)-10- (hydroxymethyl)-N-(3- methoxypheny])-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.84 C₃₁H₃₄N₃O₃ [M + H]+ 496.252: 496.50 57

(8R,9S,10S)-10- (aminomethyl)-N-(4- methoxyphenyl)-9-{4- [2-(pyridin-2-yl)ethynyl]phenyl}- 1,6- diazabicyclo[6.2.0] decane-6-carboxamide MethodA 0.49 C₃₀H₃₃N₅O₂ [M + H]+ 495.263: 495.20 58

(8R,9S,10S)-10- (acetamidomethyl)-N- (4-methoxyphenyl)-9- [4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.79 C₃₃H₃₇N₄O₃ [M + H]+ 537.28: 537.27 59

(8R,9R,10S)-10- (hydroxymethyl)-9-[4- (2- phenylethynyl)phenyl]-N-(pyridin-3-yl)-1,6- diazabicyclo[6.2.0] decane-6-carboxamide Method A0.76 C₂₉H₃₀N₄O₂ [M − H]− 466.237: 465.41 60

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-{4-[2-(pyridin-3- yl)ethynyl]phenyl}- 1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.71 C₃₀H₃₃N₄O₃ [M + H]+ 497.24: 497.49 61

(8R,9S,10S)-N-(4- methoxyphenyl)-10- [(methylamino)methyl]- 9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.65 C₃₂H₃₇N₄O₂ [M + H]+ 509.284: 509.07 62

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-N- methyl-9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.85 C₃₂H₃₆N₃O₃ [M + H]+ 510.27: 510.48 63

[(8R,9R,10S)-6-[(4- methoxyphenyl)methyl]- 9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decan-10-yl]methanolMethod A 0.99 C₃₁H₃₅N₂O₂ [M + H]+ 467.26: 467.51 64

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-[4-(pyridin-3-yl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.64 C₂₈H₃₃N₄O₃ [M + H]+ 473.25: 473.47 65

(8R,9S,10S)-10- (acetamidomethyl)-N- (4-methoxyphenyl)-9-{4-[2-(pyridin-2- yl)ethynyl]phenyl}- 1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.67 C₃₂H₃₆N₅O₃ [M + H]+ 538.27: 538.20 66

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-[4-(1-phenyl-1H-pyrrol-3- yl)phenyl]-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.82 C₃₃H₃₇N₄O₃ [M + H]+ 537.28: 537.54 67

(8R,9R,10S)-9-[4-(3- fluorophenyl)phenyl]- 10-(hydroxymethyl)-N-(4-methoxyphenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamide MethodA 0.79 C₂₉H₃₃FN₃O₃ [M + H]+ 490.243: 490.49 68

(8R,9S,10S)-10- [(dimethylamino)methyl]- N-(4- methoxyphenyl)-9-[4- (2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.93 C₃₃H₃₉N₄O₂ [M + H]+ 523.299: 523.63 69

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-[4-(pyridin-4-yl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.64 C₂₈H₃₃N₄O₃ [M + H]+ 473.25: 473.49 70

(8R,9S)-N-(4- methoxyphenyl)-9-[4- (2- phenylethynyl)phenyl]- 1,6-diazabicyclo[6.2.0] decane-6-carboxamide Method B 2.14 C₃₀H₃₂N₃O₂ [M +H]+ 466.24: 466.30 71

(8R,9R,10S)-9-{4-[2- (3,4- difluorophenyl)ethynyl] phenyl}-10-(hydroxymethyl)-N-(4- methoxyphenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.82 C₃₁H₃₂F₂N₃O₃ [M + H]+ 532.233: 532.4372

(8R,9R,10S)-9-{4-[2- (2- fluorophenyl)ethynyl] phenyl}-10-(hydroxymethyl)-N-(4- methoxyphenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.82 C₃₁H₃₃FN₃O₃ [M + H]+ 514.24: 514.4973

(8R,9S,10S)-10-[(3- hydroxy-3- methylazetidin-1- yl)methyl]-N-(4-methoxyphenyl)-9-[4- (2- phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.85 C₃₅H₄₁N₄O₃ [M + H]+ 565.31: 565.20 74

(9R,10R,11S)-11- (hydroxymethyl)-N-(4- methoxyphenyl)-10-[4- (2-phenylethynyl)phenyl]- 1,7- diazabicyclo[7.2.0] undecane-7-carboxamideMethod A 0.84 C₃₂H₃₆N₃O₃ [M + H]+ 510.27: 510.30 75

(8R,9R,10S)-9-{4-[2- (2,4- difluorophenyl)ethynyl] phenyl}-10-(hydroxymethyl)-N-(4- methoxyphenyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.81 C₃₁H₃₂F₂N₃O₃ [M + H]+ 532.23: 532.4476

(8R,9S,10S)-N-(4- methoxyphenyl)-10- [(N- methylacetamido)methyl]-9-[4-(2- phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.85 C₃₄H₃₉N₄O₃ [M + H]+ 551.294: 551.5577

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-[4-(1-phenyl-1H-pyrazol- 3-yl)phenyl]-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.75 C₃₂H₃₅N₅O₃ [M + H]+ 537.274: 538.4878

(8R,9R,10S)-10- (hydroxymethyl)-N- phenyl-9-[4-(2-phenylethynyl)phenyl]- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.85 C₃₀H₃₂N₃O₂ [M + H]+ 466.24: 466.46 79

(7R,8R,9S)-9- (hydroxymethyl)-N-(4- methoxyphenyl)-8-[4- (2-phenylethynyl)phenyl]- 1,5- diazabicyclo[5.2.0] nonane-5-carboxamideMethod A 0.79 C₃₀H₃₂N₃O₃ [M + H]+ 482.24: 482.47 80

3-(((8R,9R,10S)-6-((4- methoxyphenyl) carbamoyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decan-10-yl)methoxy)propanoic acid Method B 1.5 C₃₄H₃₇N₃O₅ [M + H]+ 568.27:568.58 81

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- methoxyphenyl)-9-(5-(phenylethynyl)pyridin- 2-yl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.77 C₃₀H₃₂N₄O₃ [M + H]+ 497.25: 497.15 82

(8R,9S,10R)-10- (acetamidomethyl)-N- (4-methoxyphenyl)-9- (4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.78 C₃₃H₃₆N₄O₃ [M + H]+ 537.28: 537.16 83

(8R,9R,10S)-10- (hydroxymethyl)-N-(4- (2- morpholinoethoxy)phenyl)-9-(4- (phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method A 0.78 C₃₆H₄₂N₄O₄ [M + H]+ 595.32: 595.46 84

(8R,9S,10R)-N-(4- methoxyphenyl)-10- (morpholinomethyl)-9- (4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod A 0.88 C₃₅H₄₀N₄O₃ [M + H]+ 565.31: 565.46 85

2-(((8R,9R,10R)-6-((4- methoxyphenyl) carbamoyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decan-10-yl)methoxy)acetic acid Method A 0.51 C₃₃H₃₅N₃O₅ [M + H]+ 554.26: 554.4186

3-(((8R,9R,10R)-6-((4- methoxyphenyl) carbamoyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decan-10-yl)methoxy)propanoic acid Method A 0.51 C₃₄H₃₇N₃O₅ [M + H]+ 568.27:568.40 87

methyl 3- (((8R,9R,10S)-6-((4- methoxyphenyl) carbamoyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decan-10-yl)methoxy)propanoate Method B 1.62 C₃₅H₃₉N₃O₅ [M + H]+ 582.29: 582.5188

(8R,9S,10R)-N-(4- methoxyphenyl)-10- ((methylamino)methyl)- 9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod B 1.86 C₃₂H₃₆N₄O₂ [M + H]+ 509.28: 509.61 89

(8R,9R,10S)-N-(4- methoxyphenyl)-10- ((3-morpholino-3-oxopropoxy)methyl)-9- (4- (phenylethynyl)phenyl)- 1,6-diazabicyclo[6.2.0] decane-6-carboxamide Method B 1.89 C₃₈H₄₄N₄O₅ [M +H]+ 637.33: 637.69 90

(8R,9S,10S)-N-(4- methoxyphenyl)-9-(4- (phenylethynyl)phenyl)-10-(((2,2,2- trifluoroethyl)amino) methyl)-1,6- diazabicyclo[6.2.0]decane-6-carboxamide Method B 2.16 C₃₃H₃₅F₃N₄O₂ [M + H]+ 577.27: 577.6391

(8R,9R,10R)-N-(4- methoxyphenyl)-10- ((3-morpholino-3-oxopropoxy)methyl)-9- (4- (phenylethynyl)phenyl)- 1,6-diazabicyclo[6.2.0] decane-6-carboxamide Method B 1.87 C₃₈H₄₄N₄O₅ [M +H]+ 637.33: 637.53 92

(8R,95S,10R)-10- ((dimethylamino) methyl)-N-(4- methoxyphenyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod B 2.06 C₃₃H₃₈N₄O₂ [M + H]+ 523.30: 523.05 93

(8R,9R,10S)-N-(4- cyanophenyl)-10- (hydroxymethyl)-9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod B 1.84 C₃₁H₃₀N₄O₂ [M + H]+ 491.24: 491.57 94

(8R,9S,10S)-10- ((diethylamino)methyl)- N-(4-methoxyphenyl)- 9-(4-(phenylethynyl)phenyl)- 1,6- diazabicyclo[6.2.0] decane-6-carboxamideMethod B 2.35 C₃₅H₄₂N₄O₂ [M + H]+ 551.33: 551.04 95

1-(((2R,3R,4S)-4- (hydroxymethyl)-1- methyl-3-(4- (phenylethynyl)phenyl)azetidin-2-yl)methyl)- 3-(4-methoxyphenyl)- 1-methylurea Method B 1.72C₂₉H₃₁N₃O₃ [M + H]+ 470.24: 470.33

In another aspect, the invention features a pharmaceutical compositionincluding a therapeutically effective amount of a compound having thestructure:

wherein the dotted line represents an optional double bond;

m is 0 or 1;

n is 0, 1, or 2;

A is CH or N;

X is absent or —C≡C—;

R¹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Y is C₁-C₆ alkylene, —C(O)NR⁴—; —SO₂—, or —C(O)—;

R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryl C₁-C₆ alkyl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;

R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl;

R⁴ is hydrogen or C₁-C₆ alkyl;

R⁵ and R⁶ are independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ acyl; and

R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉ heterocyclyl;

or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable excipient.

In some embodiments, the compound is any one of compounds 1 to 94 inTable 1 or a pharmaceutically acceptable salt thereof.

In another aspect, the invention features a pharmaceutical compositionincluding a therapeutically effective amount of compound 95 of Table 1or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.

In another aspect, the invention features a method of preventing ortreating malaria (e.g., malaria caused by P. falciparum, P. vivax, P.ovale, P. malariae, or P. knowlesi) in a subject. This method includesthe step of administering to the subject an effective amount of acompound having the structure:

wherein the dotted line represents an optional double bond;

m is 0 or 1;

n is 0, 1, or 2;

A is CH or N;

X is absent or —C≡C—;

R¹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Y is C₁-C₆ alkylene, —C(O)NR⁴—; —SO₂—, or —C(O)—;

R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryl C₁-C₆ alkyl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;

R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl;

R⁴ is hydrogen or C₁-C₆ alkyl;

R⁵ and R⁶ are independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ acyl; and

R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉ heterocyclyl;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is any one of compounds 1 to 94 ofTable 1 or a pharmaceutically acceptable salt thereof.

In some embodiments of any of the foregoing methods, the malaria is drugresistant (e.g., the malaria is resistant to chloroquine, quinine,pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine,artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil,doxycycline, clindamycin, artemisinin, atovaquone, or any combinationthereof).

In some embodiments, the malaria is liver stage (also known as hepaticstage malaria). In other embodiments, the malaria is blood stage (alsoknown as erythrocytic stage malaria). In some embodiments, the malariais transmission stage (i.e., the stage in which transmission of theparasite back to a mosquito occurs also known as gametocytic stagemalaria).

In another aspect, the invention features a method of preventing ortreating malaria (e.g., malaria caused by P. falciparum, P. vivax, P.ovale, P. malariae, or P. knowlesi) in a subject. This method includesthe step of administering to the subject an effective amount of acompound 95 or a pharmaceutically acceptable salt thereof.

In some embodiments of any of the foregoing methods, the malaria is drugresistant (e.g., the malaria is resistant to chloroquine, quinine,pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine,artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil,doxycycline, clindamycin, artemisinin, atovaquone, or any combinationthereof).

In some embodiments, the malaria is hepatic. In other embodiments, themalaria is blood stage. In some embodiments, the invention concernspreventing transmission of malaria back to the mosquito.

In another aspect, the invention features a compound according toFormula VIII:

wherein:

n is 0, 1, 2 or 3;

X is a single bond, hydrogen, —C≡C—, thiazolyl, pyrrolyl, pyrazolyl,pyridinyl, phenyl monosubstituted with —F or phenyl disubstituted withhalogen or absent;

Y is —CH₂—, —C(O)NH—, —S(O)₂—, —CH₂CH₂—, —S(O)₂CH₂—, —C(O)—, or—C(O)N(CH₃)—;

R₁ is pyridinyl, cyclopropyl, —CH(CH₃)₂, —OCH₃, cyclopentyl, cyclohexyl,cyclohexenyl, unsubstituted phenyl, phenyl monosubstituted with —CH₃,—OCH₃ or halogen, phenyl disubstituted with halogen or absent;

R₂ is —CF₃, cyclohexyl, pyridinyl, unsubstituted phenyl or phenylsubstituted with —CH₃, —OCH₃ or halogen;

R₃ is hydrogen, —C(O)OH or —CH₂—R₄; and

R₄ is hydroxy, methylpiperazinyl, hydroxymethylpiperidinyl, —OCH₂C(O)OH,—NH₂, —C(O)OH, morpholinyl, —NHC(O)CH₃, —NHCH₃, —N(CH₃)₂,hydroxymethylazetidinyl or —N(CH₃)C(O)CH₃,

or a pharmaceutically acceptable salt thereof,

with the proviso that said compound is not any one of compounds 1 to 30of Table 1.

In some embodiments, n is 1, 2 or 3. In other embodiments, n is 2. Incertain embodiments, X is a single bond, hydrogen, or —C≡C—. In someembodiments, X is thiazolyl, pyrrolyl or pyrazolyl. In otherembodiments, X is —C≡C—. In certain embodiments, R₁ is pyridinyl,cyclopropyl, —CH(CH₃)₂, —OCH₃, cyclopentyl, cyclohexyl, cyclohexenyl orabsent. In some embodiments, R₁ is unsubstituted phenyl, phenylmonosubstituted with —CH₃, —OCH₃ or halogen or phenyl disubstituted withhalogen. In other embodiments, R₁ is unsubstituted phenyl. In certainembodiments, Y is —C(O)NH— or —C(O)N(CH₃)—. In some embodiments, R₂ is—CF₃, cyclohexyl or pyridinyl. In other embodiments, R₂ is unsubstitutedphenyl or phenyl substituted with —CH₃, —OCH₃ or halogen. In certainembodiments, R₃ is —CH₂—R₄. In some embodiments, R₄ is hydroxy,—OCH₂C(O)OH, —NH₂, —C(O)OH, —NHC(O)CH₃, —NHCH₃, —N(CH₃)₂, or—N(CH₃)C(O)CH₃. In some embodiments, R₄ is methylpiperazinyl,hydroxymethylpiperidinyl, morpholinyl or hydroxymethylazetidinyl. Inother embodiments, R₄ is hydroxy. In certain embodiments, said compoundis any one of compounds 31 to 95 of Table 1.

In another aspect, the invention features a pharmaceutical composition,comprising a therapeutically effective amount of a compound according toFormula VIII:

wherein:

n is 0, 1, 2 or 3;

X is a single bond, hydrogen, —C≡C—, thiazolyl, pyrrolyl, pyrazolyl,pyridinyl, phenyl monosubstituted with —F or phenyl disubstituted withhalogen or absent;

Y is —CH₂—, —C(O)NH—, —S(O)₂—, —CH₂CH₂—, —S(O)₂CH₂—, —C(O)—, or—C(O)N(CH₃)—;

R₁ is pyridinyl, cyclopropyl, —CH(CH₃)₂, —OCH₃, cyclopentyl, cyclohexyl,cyclohexenyl, unsubstituted phenyl, phenyl monosubstituted with —CH₃,—OCH₃ or halogen, phenyl disubstituted with halogen or absent;

R₂ is —CF₃, cyclohexyl, pyridinyl, unsubstituted phenyl or phenylsubstituted with —CH₃, —OCH₃ or halogen;

R₃ is hydrogen, —C(O)OH or —CH₂—R₄; and

R₄ is hydroxy, methylpiperazinyl, hydroxymethylpiperidinyl, —OCH₂C(O)OH,—NH₂, —C(O)OH, morpholinyl, —NHC(O)CH₃, —NHCH₃, —N(CH₃)₂,hydroxymethylazetidinyl or —N(CH₃)C(O)CH₃,

or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

In another aspect, the invention features a method of treating malaria,comprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound according to FormulaVIII:

wherein:

n is 0, 1, 2 or 3;

X is a single bond, hydrogen, —C≡C—, thiazolyl, pyrrolyl, pyrazolyl,pyridinyl, phenyl monosubstituted with —F or phenyl disubstituted withhalogen or absent;

Y is —CH₂—, —C(O)NH—, —S(O)₂—, —CH₂CH₂—, —S(O)₂CH₂—, —C(O)—, or—C(O)N(CH₃)—;

R₁ is pyridinyl, cyclopropyl, —CH(CH₃)₂, —OCH₃, cyclopentyl, cyclohexyl,cyclohexenyl, unsubstituted phenyl, phenyl monosubstituted with —CH₃,—OCH₃ or halogen, phenyl disubstituted with halogen or absent;

R₂ is —CF₃, cyclohexyl, pyridinyl, unsubstituted phenyl or phenylsubstituted with —CH₃, —OCH₃ or halogen;

R₃ is hydrogen, —C(O)OH or —CH₂—R₄; and

R₄ is hydroxy, methylpiperazinyl, hydroxymethylpiperidinyl, —OCH₂C(O)OH,—NH₂, —C(O)OH, morpholinyl, —NHC(O)CH₃, —NHCH₃, —N(CH₃)₂,hydroxymethylazetidinyl or —N(CH₃)C(O)CH₃,

or a pharmaceutically acceptable salt thereof.

The present invention is also directed to pharmaceutical compositionsand to methods of treating malaria including/using a compound asdescribed above or elsewhere herein.

Chemical Terms

It is to be understood that the terminology employed herein is for thepurpose of describing particular embodiments, and is not intended to belimiting. Further, although any methods and materials similar orequivalent to those described herein can be used in the practice ortesting of the invention, the preferred methods and materials are nowdescribed.

The term “acyl,” as used herein, represents a hydrogen or an alkylgroup, as defined herein, that is attached to the parent molecular groupthrough a carbonyl group, as defined herein, and is exemplified byformyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl,propionyl, and butanoyl. Exemplary unsubstituted acyl groups includefrom 1 to 6, from 1 to 11, or from 1 to 21 carbons. In some embodiments,the alkyl group is further substituted with 1, 2, 3, or 4 substituentsas described herein.

As used herein, the term “alkyl,” alone or in combination with othergroups, refers to a branched or straight-chain monovalent saturatedaliphatic hydrocarbon radical of one to twenty carbon atoms (e.g., oneto sixteen carbon atoms, one to ten carbon atoms, or one to six carbonatoms).

The term “alkylene” as used herein, represents a saturated divalenthydrocarbon group derived from a straight or branched chain saturatedhydrocarbon by the removal of two hydrogen atoms, and is exemplified bymethylene, ethylene, and isopropylene. In some embodiments, the alkylenecan be further substituted with 1, 2, 3, or 4 substituent groups asdefined herein for an alkyl group.

As used herein, the term “alkenyl,” alone or in combination with othergroups, refers to a straight-chain or branched hydrocarbon residuehaving an olefinic bond.

The term “amino,” as used herein, represents —N(R^(N1))₂, wherein eachR^(N1) is, independently, H, OH, NO₂, N(R^(N2))₂, SO₂OR^(N2), SO₂RN²,SOR^(N2), an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl,alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionallysubstituted with an 0-protecting group, such as optionally substitutedarylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl(e.g., acetyl, trifluoroacetyl, or others described herein),alkoxycarbonylalkyl (e.g., optionally substituted with an O-protectinggroup, such as optionally substituted arylalkoxycarbonyl groups or anydescribed herein), heterocyclyl (e.g., heteroaryl), or heterocyclylalkyl(e.g., heteroarylalkyl), wherein each of these recited R^(N1) groups canbe optionally substituted, as defined herein for each group; or twoR^(N1) combine to form a heterocyclyl or an N-protecting group, andwherein each R^(N2) is, independently, H, alkyl, or aryl. The aminogroups of the invention can be an unsubstituted amino (i.e., —NH₂) or asubstituted amino (i.e., —N(R^(N1))₂). In a preferred embodiment, aminois —NH₂ or —NHR^(N1), wherein R^(N1) is, independently, OH, NO₂, NH₂,NR^(N2), SO₂OR^(N2), SO₂R^(N2), SOR^(N2), alkyl, carboxyalkyl,sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others describedherein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, andeach R^(N2) can be H, C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), or C₆₋₁₀ aryl.

The term “aryl” refers to an aromatic mono- or polycyclic radical of 6to 12 carbon atoms having at least one aromatic ring. Examples of suchgroups include, but are not limited to, phenyl, naphthyl,1,2,3,4-tetrahydronaphthalyl, 1,2-dihydronaphthalyl, indanyl, and1H-indenyl.

The “arylalkyl” group, which as used herein, represents an aryl group,as defined herein, attached to the parent molecular group through analkylene group, as defined herein. Exemplary unsubstituted arylalkylgroups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20carbons, such as C₆₋₁₀ aryl C₁₋₆ alkyl, C₆₋₁₀ aryl C₁₋₁₀ alkyl, or C₆₋₁₀aryl C₁₋₂₀ alkyl). In some embodiments, the alkylene and the aryl eachcan be further substituted with 1, 2, 3, or 4 substituent groups asdefined herein for the respective groups.

The alkyl, carbocyclic, and aryl groups may be substituted orunsubstituted. When substituted, there will generally be, for example, 1to 4 substituents present. These substituents may optionally form a ringwith the alkyl, carbocyclic, or aryl group with which they areconnected. Substituents may include, for example: carbon-containinggroups such as alkyl, aryl, arylalkyl (e.g., substituted andunsubstituted phenyl, substituted and unsubstituted benzyl); halogenatoms and halogen-containing groups such as haloalkyl (e.g.,trifluoromethyl); oxygen-containing groups such as alcohols (e.g.,hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g., alkoxy,aryloxy, alkoxyalkyl, alkoxyheterocyclyl, aryloxyalkyl, more preferably,for example, methoxy and ethoxy), aldehydes (e.g., carboxaldehyde),ketones (e.g., alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,arylalkylcarbonyl, arylcarbonylalkyl), acids (e.g., carboxy,carboxyalkyl), acid derivatives such as esters (e.g., alkoxycarbonyl,alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides(e.g., aminocarbonyl, mono- or di-alkylaminocarbonyl,aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl,arylaminocarbonyl), carbamates (e.g., alkoxycarbonylamino,aryloxycarbonylamino, aminocarbonyloxy, mono- ordi-alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (e.g., mono- ordi-alkylaminocarbonylamino or arylaminocarbonylamino);nitrogen-containing groups such as amines (e.g., amino, mono- ordi-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides,nitriles (e.g., cyano, cyanoalkyl), nitro; sulfur-containing groups suchas thiols, thioethers, sulfoxides and sulfones (e.g., alkylthio,alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl,arylsulfinylalkyl, arylsulfonylalkyl); heterocyclyl heteroalkyl groups,and heterocyclic groups containing one or more heteroatoms, (e.g.,thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl,azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl,pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl,thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl,isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl,coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl,cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl,chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).

The term “azido” represents an —N₃ group, which can also be representedas —N═N═N.

The terms “carbocyclic” and “carbocyclyl,” as used herein, refer to anoptionally substituted non-aromatic C₃₋₁₂ monocyclic, bicyclic, ortricyclic structure in which the rings are formed by carbon atoms.Carbocyclic structures include cycloalkyl, cycloalkenyl, andcycloalkynyl groups.

The term “cycloalkyl” refers to a monovalent mono- or polycarbocyclicradical of three to ten, preferably three to six carbon atoms. This termis further exemplified by radicals such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and indanyl.In a preferred embodiment, the “cycloalkyl” moieties can optionally besubstituted with one, two, three or four substituents. Each substituentcan independently be, alkyl, alkoxy, halogen, amino, hydroxyl or oxygenunless otherwise specifically indicated. Examples of cycloalkyl moietiesinclude, but are not limited to, optionally substituted cyclopropyl,optionally substituted cyclobutyl, optionally substituted cyclopentyl,optionally substituted cyclopentenyl, optionally substituted cyclohexyl,and optionally substituted cycloheptyl, or those which are specificallyexemplified herein.

The term “cyano,” as used herein, represents a —CN group.

As used herein, the term “halo” or “halogen” means a fluorine (fluoro),chlorine (chloro), bromine (bromo) or iodine (iodo) radical.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, in which one or more of the constituent carbon atomshave each been replaced by nitrogen, oxygen, or sulfur. In someembodiments, the heteroalkyl group can be further substituted with 1, 2,3, or 4 substituent groups as described herein for alkyl groups.Examples of heteroalkyl groups are an “alkoxy” which, as used herein,refers alkyl-O—; and “alkoyl” which, as used herein, refers toalkyl-CO—. Alkoxy substituent groups or alkoxy-containing substituentgroups may be substituted by, for example, one or more alkyl groups.

The term “heteroaryl,” refers to an aromatic mono- or polycyclic radicalof 5 to 12 atoms having at least one aromatic ring containing one, two,or three ring heteroatoms selected from N, O, and S, with the remainingring atoms being C. One or two ring carbon atoms of the heteroaryl groupmay be replaced with a carbonyl group. Examples of heteroaryl groups arebenzooxazolyl, benzoimidazolyl, and benzothiazolyl.

The term “heterocycle” or “heterocyclyl” denotes a mono- or polycyclicalkyl ring, wherein one, two or three of the carbon ring atoms isreplaced by a heteroatom such as N, O or S. Examples of hetereocyclylgroups include, but are not limited to, morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrofuranyl, and 1,3-dioxanyl. The heterocyclyl groups may beunsubstituted or substituted, and attachment may be through their carbonframe or through their heteroatom(s) where appropriate.

The term “heterocyclyl heteroalkyl” refers to a heterocyclic group, asdefined herein, attached to the parent molecular group through aheteroalkyl group (e.g., an ether or alkoxy group). An example of aheterocyclyl heteroalkyl group is —OCH₂CH₂(morpholino) group.

The heterocyclyl and heteroaryl groups described above may besubstituted independently with one, two, three, or more substituents.Substituents may include, for example: carbon-containing groups such asalkyl, aryl, arylalkyl (e.g., substituted and unsubstituted phenyl,substituted and unsubstituted benzyl); halogen atoms andhalogen-containing groups such as haloalkyl (e.g., trifluoromethyl);oxygen-containing groups such as alcohols (e.g., hydroxyl, hydroxyalkyl,aryl(hydroxyl)alkyl), ethers (e.g., alkoxy, aryloxy, alkoxyalkyl,aryloxyalkyl), aldehydes (e.g., carboxaldehyde), ketones (e.g.,alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl,arylcarbonylalkyl), acids (e.g., carboxy, carboxyalkyl), acidderivatives such as esters (e.g., alkoxycarbonyl, alkoxycarbonylalkyl,alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g., aminocarbonyl,mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- ordi-alkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (e.g.,alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- ordi-alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (e.g., mono- ordi-alkylaminocarbonylamino or arylaminocarbonylamino);nitrogen-containing groups such as amines (e.g., amino, mono- ordi-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides,nitriles (e.g., cyano, cyanoalkyl), nitro; sulfur-containing groups suchas thiols, thioethers, sulfoxides and sulfones (e.g., alkylthio,alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl,arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groupscontaining one or more heteroatoms, (e.g., thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl,thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl,pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl,piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl,indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl,benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl,naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl,benzothiazolyl and carbolinyl).

The term “hydroxyl,” as used herein, represents an —OH group. In someembodiments, the hydroxyl group can be substituted with a O-protectinggroup as defined herein.

The term “N-protecting group,” as used herein, represents those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Commonly used N-protecting groups are disclosed inGreene, “Protective Groups in Organic Synthesis,” 3^(rd) Edition (JohnWiley & Sons, New York, 1999), which is incorporated herein byreference. N-protecting groups include acyl, aryloyl, or carbamyl groupssuch as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliariessuch as protected or unprotected D, L or D, L-amino acids such asalanine, leucine, and phenylalanine; sulfonyl-containing groups such asbenzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such asbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl,alkaryl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, andsilyl groups, such as trimethylsilyl. Preferred N-protecting groups arealloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl(Cbz).

The term “O-protecting group,” as used herein, represents those groupsintended to protect an oxygen containing (e.g., phenol, hydroxyl, orcarbonyl) group against undesirable reactions during syntheticprocedures. Commonly used O-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3^(rd) Edition (John Wiley &Sons, New York, 1999), which is incorporated herein by reference.Exemplary O-protecting groups include acyl, aryloyl, or carbamyl groups,such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl,tri-iso-propylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl,phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and4-nitrobenzoyl; alkylcarbonyl groups, such as acyl, acetyl, propionyl,and pivaloyl; optionally substituted arylcarbonyl groups, such asbenzoyl; silyl groups, such as trimethylsilyl (TMS),tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), andtriisopropylsilyl (TIPS); ether-forming groups with the hydroxyl, suchmethyl, methoxymethyl, tetrahydropyranyl, benzyl, p-methoxybenzyl, andtrityl; alkoxycarbonyls, such as methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, n-isopropoxycarbonyl, n-butyloxycarbonyl,isobutyloxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl,2-ethylhexyloxycarbonyl, cyclohexyloxycarbonyl, and methyloxycarbonyl;alkoxyalkoxycarbonyl groups, such as methoxymethoxycarbonyl,ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl,2-butoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl,allyloxycarbonyl, propargyloxycarbonyl, 2-butenoxycarbonyl, and3-methyl-2-butenoxycarbonyl; haloalkoxycarbonyls, such as2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, and2,2,2-trichloroethoxycarbonyl; optionally substituted arylalkoxycarbonylgroups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-bromobenzyloxy-carbonyl, andfluorenylmethyloxycarbonyl; and optionally substituted aryloxycarbonylgroups, such as phenoxycarbonyl, p-nitrophenoxycarbonyl,o-nitrophenoxycarbonyl, 2,4-dinitrophenoxycarbonyl,p-methyl-phenoxycarbonyl, m-methylphenoxycarbonyl,o-bromophenoxycarbonyl, 3,5-dimethylphenoxycarbonyl,p-chlorophenoxycarbonyl, and 2-chloro-4-nitrophenoxy-carbonyl);substituted alkyl, aryl, and alkaryl ethers (e.g., trityl;methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl;2,2,2-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl;ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl;t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl,p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl;triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl;t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl;triphenylsilyl; and diphenymethylsilyl); carbonates (e.g., methyl,methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl;2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl;methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl);carbonyl-protecting groups (e.g., acetal and ketal groups, such asdimethyl acetal, and 1,3-dioxolane; acylal groups; and dithiane groups,such as 1,3-dithianes, and 1,3-dithiolane); carboxylic acid-protectinggroups (e.g., ester groups, such as methyl ester, benzyl ester, t-butylester, and orthoesters; and oxazoline groups.

The term “perfluoroalkyl,” as used herein, represents alkyl group, asdefined herein, where each hydrogen radical bound to the alkyl group hasbeen replaced by a fluoride radical. For example, perfluoroalkyl groupsare exemplified by trifluoromethyl and pentafluoroethyl.

The term “sulfonyl,” as used herein, represents an —S(O)₂— group.

Compounds of the invention can have one or more asymmetric carbon atomsand can exist in the form of optically pure enantiomers, mixtures ofenantiomers such as racemates, optically pure diastereoisomers, mixturesof diastereoisomers, diastereoisomeric racemates or mixtures ofdiastereoisomeric racemates. The optically active forms can be obtainedfor example by resolution of the racemates, by asymmetric synthesis orasymmetric chromatography (chromatography with a chiral adsorbents oreluant). That is, certain of the disclosed compounds may exist invarious stereoisomeric forms. Stereoisomers are compounds that differonly in their spatial arrangement. Enantiomers are pairs ofstereoisomers whose mirror images are not superimposable, most commonlybecause they contain an asymmetrically substituted carbon atom that actsas a chiral center. “Enantiomer” means one of a pair of molecules thatare mirror images of each other and are not superimposable.Diastereomers are stereoisomers that are not related as mirror images,most commonly because they contain two or more asymmetricallysubstituted carbon atoms and represent the configuration of substituentsaround one or more chiral carbon atoms. Enantiomers of a compound can beprepared, for example, by separating an enantiomer from a racemate usingone or more well-known techniques and methods, such as chiralchromatography and separation methods based thereon. The appropriatetechnique and/or method for separating an enantiomer of a compounddescribed herein from a racemic mixture can be readily determined bythose of skill in the art. “Racemate” or “racemic mixture” means amixture containing two enantiomers, wherein such mixtures exhibit nooptical activity; i.e., they do not rotate the plane of polarized light.“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration. “R,” “S,”“S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurationsrelative to the core molecule. Certain of the disclosed compounds mayexist in atropisomeric forms. Atropisomers are stereoisomers resultingfrom hindered rotation about single bonds where the steric strainbarrier to rotation is high enough to allow for the isolation of theconformers. The compounds of the invention may be prepared as individualisomers by either isomer-specific synthesis or resolved from an isomericmixture. Conventional resolution techniques include forming the salt ofa free base of each isomer of an isomeric pair using an optically activeacid (followed by fractional crystallization and regeneration of thefree base), forming the salt of the acid form of each isomer of anisomeric pair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods. When the stereochemistry of a disclosedcompound is named or depicted by structure, the named or depictedstereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9%) by weightrelative to the other stereoisomers. When a single enantiomer is namedor depicted by structure, the depicted or named enantiomer is at least60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When asingle diastereomer is named or depicted by structure, the depicted ornamed diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% byweight pure. Percent optical purity is the ratio of the weight of theenantiomer or over the weight of the enantiomer plus the weight of itsoptical isomer. Diastereomeric purity by weight is the ratio of theweight of one diastereomer or over the weight of all the diastereomers.When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure relative to the otherstereoisomers. When a single enantiomer is named or depicted bystructure, the depicted or named enantiomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer isnamed or depicted by structure, the depicted or named diastereomer is atleast 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percentpurity by mole fraction is the ratio of the moles of the enantiomer orover the moles of the enantiomer plus the moles of its optical isomer.Similarly, percent purity by moles fraction is the ratio of the moles ofthe diastereomer or over the moles of the diastereomer plus the moles ofits isomer. When a disclosed compound is named or depicted by structurewithout indicating the stereochemistry, and the compound has at leastone chiral center, it is to be understood that the name or structureencompasses either enantiomer of the compound free from thecorresponding optical isomer, a racemic mixture of the compound ormixtures enriched in one enantiomer relative to its correspondingoptical isomer. When a disclosed compound is named or depicted bystructure without indicating the stereochemistry and has two or morechiral centers, it is to be understood that the name or structureencompasses a diastereomer free of other diastereomers, a number ofdiastereomers free from other diastereomeric pairs, mixtures ofdiastereomers, mixtures of diastereomeric pairs, mixtures ofdiastereomers in which one diastereomer is enriched relative to theother diastereomer(s) or mixtures of diastereomers in which one or morediastereomer is enriched relative to the other diastereomers. Theinvention embraces all of these forms.

Definitions

The term “effective amount” of an agent, as used herein, is that amountsufficient to effect beneficial or desired results, such as clinicalresults, and, as such, an “effective amount” depends upon the context inwhich it is being applied. For example, in the context of administeringan agent that is an antimalarial agent, an effective amount of an agentis, for example, an amount sufficient to achieve alleviation oramelioration of one or more symptoms or conditions; diminishment ofextent of disease, disorder, or condition; stabilized (i.e., notworsening) state of disease, disorder, or condition; preventing spreadof disease, disorder, or condition (e.g., preventing the spread ofPlasmodium infection beyond the liver, preventing systemic disease,preventing the symptomatic stage of malaria, preventing establishment ofPlasmodium infection and/or preventing further spread of the disease bypreventing transmission back to the mosquito); delay or slowing theprogress of the disease, disorder, or condition; amelioration orpalliation of the disease, disorder, or condition; and remission(whether partial or total), whether detectable or undetectable, ascompared to the response obtained without administration of the agent.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with apharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition is manufactured or sold with the approval ofa governmental regulatory agency as part of a therapeutic regimen forthe treatment of disease in a mammal. Pharmaceutical compositions can beformulated, for example, for oral administration in unit dosage form(e.g., a tablet, capsule, caplet, gelcap, or syrup); for topicaladministration (e.g., as a cream, gel, lotion, or ointment); forintravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other formulation described herein (see below).

Useful pharmaceutical carriers for the preparation of the compositionshereof, can be solids, liquids, or gases. Thus, the compositions cantake the form of tablets, pills, capsules, suppositories, powders,enterically coated or other protected formulations (e.g., binding onion-exchange resins or packaging in lipid-protein vesicles), sustainedrelease formulations, solutions, suspensions, elixirs, and aerosols. Thecarrier can be selected from the various oils including those ofpetroleum, animal, vegetable or synthetic origin, e.g., peanut oil,soybean oil, mineral oil, and sesame oil. Water, saline, aqueousdextrose, and glycols are preferred liquid carriers, particularly (whenisotonic with the blood) for injectable solutions. For example,formulations for intravenous administration comprise sterile aqueoussolutions of the active ingredient(s) which are prepared by dissolvingsolid active ingredient(s) in water to produce an aqueous solution, andrendering the solution sterile. Suitable pharmaceutical excipientsinclude starch, cellulose, talc, glucose, lactose, talc, gelatin, malt,rice, flour, chalk, silica, magnesium stearate, sodium stearate,glycerol monostearate, sodium chloride, dried skim milk, glycerol,propylene glycol, water, and ethanol. The compositions may be subjectedto conventional pharmaceutical additives such as preservatives,stabilizing agents, wetting or emulsifying agents, salts for adjustingosmotic pressure, and buffers. Suitable pharmaceutical carriers andtheir formulation are described in Remington's Pharmaceutical Sciencesby E. W. Martin. Such compositions will, in any event, contain aneffective amount of the active compound together with a suitable carrierso as to prepare the proper dosage form for administration to therecipient.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of any of the compounds described herein that within the scope ofsound medical judgment, are suitable for use in contact with the tissuesof humans and animals without undue toxicity, irritation, allergicresponse and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts are well known in the art. Forexample, pharmaceutically acceptable salts are described in: Berge etal., J. Pharmaceutical Sciences 66:1-19, 1977 and in PharmaceuticalSalts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G.Wermuth), Wiley-VCH, 2008. Salts may be prepared from pharmaceuticallyacceptable non-toxic acids and bases including inorganic and organicacids and bases. Representative acid addition salts include acetate,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, dichloroacetate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glutamate,glycerophosphate, hemisulfate, heptonate, hexanoate, hippurate,hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate,isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate,maleate, malonate, mandelate, methanesulfonate, mucate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pantothenate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, undecanoate, and valeratesalts. Representative basic salts include alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, and magnesium,aluminum salts, as well as nontoxic ammonium, quaternary ammonium, andamine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, caffeine, and ethylamine.

As used herein, the term “subject” refers to any organism to which acomposition in accordance with the invention may be administered, e.g.,for experimental, diagnostic, prophylactic, and/or therapeutic purposes.Typical subjects include any animal (e.g., mammals such as mice, rats,rabbits, non-human primates, and humans). A subject may seek or be inneed of treatment, require treatment, be receiving treatment, may bereceiving treatment in the future, or a human or animal that is undercare by a trained professional for a particular disease or condition.

As used herein, and as well understood in the art, “to treat” acondition or “treatment” of the condition (e.g., the conditionsdescribed herein such as malaria) is an approach for obtainingbeneficial or desired results, such as clinical results. Beneficial ordesired results can include, but are not limited to, alleviation oramelioration of one or more symptoms or conditions; diminishment ofextent of disease, disorder, or condition; stabilized (i.e., notworsening) state of disease, disorder, or condition; preventing spreadof disease, disorder, or condition (e.g., preventing the spread ofPlasmodium infection beyond the liver or preventing transmission back tothe mosquito, preventing systemic disease, preventing the symptomaticstage of malaria, and/or preventing establishment of Plasmodiuminfection); delay or slowing the progress of the disease, disorder, orcondition; amelioration or palliation of the disease, disorder, orcondition; and remission (whether partial or total), whether detectableor undetectable. “Palliating” a disease, disorder, or condition meansthat the extent and/or undesirable clinical manifestations of thedisease, disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

The term “unit dosage form” refers to a physically discrete unitsuitable as a unitary dosage for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with anysuitable pharmaceutical excipient or excipients. Exemplary, non-limitingunit dosage forms include a tablet (e.g., a chewable tablet), caplet,capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip,gelcap, and syrup (also see below).

Other features and advantages of the invention are described in thefollowing detailed description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1, Panel A, provides images of CD-1 mice inoculated with P. bergheiblood stage parasites before treatment with the indicated compounds. Agraphical representation of the results of this experiment is providedin FIG. 1, Panel B (see Example 4, below, for details).

FIG. 2, Panel A, provides microscopic images of oocysts from the midgutsof mosquitoes that were allowed to feed on mice that had been infectedwith P. berghei and then treated with vehicle or compound 37. Agraphical representation of the results of this experiment is providedin FIG. 2, Panel B (see Example 5, below, for details).

FIG. 3 provides images of CD-1 mice inoculated with P. bergheisporozoites before treatment with vehicle, ATVQ, or compound 37 (seeExample 6, below, for details).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for novel compounds and pharmaceuticalcompositions useful for the treatment of malaria. The invention alsoprovides methods of using these compounds and compositions, as well asrelated kits.

Utility and Administration

The compounds described herein are useful in the methods of theinvention and, while not bound by any particular theory, are believed toexert their desirable effects through their ability to inhibit thegrowth of or kill a parasitic protozoan that causes malaria (e.g., P.falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi). Insome embodiments, the treatment of malaria includes causativeprophylaxis, such as preventing the spread of Plasmodium infectionbeyond the liver, preventing systemic disease, preventing thesymptomatic stage of malaria, preventing the establishment of theinfection, and/or preventing further transmission (e.g., to a mosquito).In some embodiments, the treatment of malaria refers to treatmentintended to achieve cure (e.g., of P. vivax or P. malariae), e.g.,treatment for radical cure (i.e., clearing hypnozoites from the liver).In various examples, the methods include preventing spread of infectionof a malaria-causing parasite as described herein from the liver.

The compounds of the invention may be useful in the treatment of drugresistant malaria, such as malaria resistant to chloroquine, quinine,pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine,artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil,doxycycline, clindamycin, artemisinin, atovaquone, and any combinationthereof.

For use in the methods of the invention, the compounds of the inventioncan be formulated as pharmaceutical or veterinary compositions. Theformulation selected can vary depending on the subject to be treated,the mode of administration, and the type of treatment desired (e.g.,prevention, prophylaxis, or therapy). A summary of formulationtechniques is found in Remington: The Science and Practice of Pharmacy,21^(st) Edition, Lippincott Williams & Wilkins, (2005); and Encyclopediaof Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,1988-1999, Marcel Dekker, New York, each of which is incorporated hereinby reference. Exemplary routes of administration and formulations aredescribed as follows.

In the practice of the methods of the invention, the compounds (orpharmaceutically acceptable salts thereof) or compositions of theinvention can be administered by any of the usual and acceptable routesand methods known in the art. The compounds or compositions can thus beadministered, for example, by the enteral or gastrointestinal route(e.g., orally or rectally), topically (e.g., to the skin or anaccessible mucous membrane (e.g., an intraoral (e.g., sublingual orbuccal), intranasal, intrarectal, or genitourinary surface)),parenterally (e.g., by intramuscular, intravenous, subcutaneous,intraarticular, intravesicular, intrathecal, epidural, ocular, or auralapplication or injection), transdermally, or by inhalation (e.g., byaerosol).

The compositions can be in the form of a solid, liquid, or gas, asdetermined to be appropriate by those of skill in the art. Thus, asgeneral examples, the pharmaceutical compositions may be in the form oftablets, capsules, syrups, pills, enterically coated or other protectedformulations, sustained release formulations, elixirs, powders,granulates, suspensions, emulsions, solutions, gels (e.g., hydrogels),pastes, ointments, creams, plasters, transdermal patches, drenches,suppositories, enemas, injectables, implants, sprays, or aerosols.

The compositions of the invention, in general, include an effectiveamount of a compound described herein and one or more pharmaceuticallyacceptable carriers or excipients, as is well known in the art. Thecompositions can thus include one or more diluents, buffers,preservatives, salts, carbohydrates, amino acids, carrier proteins,fatty acids, lipids, etc. The compounds described herein may be presentin amounts totaling, for example, 1-95% by weight of the total weight ofthe composition.

For injection, formulations can be prepared in conventional forms asliquid solutions or suspensions, or as solid forms suitable for solutionor suspension in liquid prior to injection, or as emulsions. Suitableexcipients for these formulations include, for example, water, saline,dextrose, and glycerol. Such compositions can also contain nontoxicauxiliary substances, such as wetting or emulsifying agents, and pHbuffering agents, such as sodium acetate, sorbitan monolaurate, and soforth.

Formulations for oral use include tablets containing a compound of theinvention in a mixture with one or more non-toxic pharmaceuticallyacceptable excipients. These excipients may be, for example, inertdiluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol,microcrystalline cellulose, starches including potato starch, calciumcarbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate,or sodium phosphate); granulating and disintegrating agents (e.g.,cellulose derivatives including microcrystalline cellulose, starchesincluding potato starch, croscarmellose sodium, alginates, or alginicacid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginicacid, sodium alginate, gelatin, starch, pregelatinized starch,microcrystalline cellulose, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, andbuffering agents.

Formulations for oral use may also be provided as chewable tablets, oras hard gelatin capsules wherein the active ingredient is mixed with aninert solid diluent (e.g., potato starch, lactose, microcrystallinecellulose, calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example, peanut oil, liquid paraffin, or olive oil.Powders, granulates, and pellets may be prepared using the ingredientsmentioned above under tablets and capsules in a conventional mannerusing, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Dissolution or diffusion controlled release can be achieved byappropriate coating of a tablet, capsule, pellet, or granulateformulation of compounds, or by incorporating the compound into anappropriate matrix. A controlled release coating may include one or moreof the coating substances mentioned above and/or, e.g., shellac,beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glycerylmonostearate, glyceryl distearate, glycerol palmitostearate,ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetatebutyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone,polyethylene, polymethacrylate, methylmethacrylate,2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol,ethylene glycol methacrylate, and/or polyethylene glycols. In acontrolled release matrix formulation, the matrix material may alsoinclude, e.g., hydrated methylcellulose, carnauba wax and stearylalcohol, carbopol 934, silicone, glyceryl tristearate, methylacrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/orhalogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

The compounds and compositions of the invention can be packaged in akit, optionally with one or more other pharmaceutical agents (seebelow). Non-limiting examples of the kits include those that contain,e.g., two or more pills, a pill and a powder, a suppository and a liquidin a vial, or two topical creams. The kits can include optionalcomponents that aid in the administration of the unit dose to subjects,such as vials for reconstituting powder forms, syringes for injection,customized IV delivery systems, or inhalers. Additionally, the unit dosekits can contain instructions for preparation and administration of thecompositions. The kits can be manufactured as a single use unit dose forone subject, multiple uses for a particular subject (at a constant doseor in which the individual compounds may vary in potency as therapyprogresses); or the kits can contain multiple doses suitable foradministration to multiple subjects (“bulk packaging”). The kitcomponents can be assembled in cartons, blister packs, bottles, andtubes.

The dose of a compound of the present invention depends on a number offactors, such as the manner of administration, the age and the bodyweight of the subject, and the condition of the subject to be treated,and ultimately will be decided by the attending physician orveterinarian. Such an amount of the compound, as determined by theattending physician or veterinarian, is referred to herein, and in theclaims, as a “therapeutically effective amount.” For example, the doseof a compound of the present invention is typically in the range ofabout 1 to about 1000 mg per day. Preferably, the therapeuticallyeffective amount is in an amount of from about 1 mg to about 500 mg perday.

Administration of each drug, as described herein, can, independently, beone to four times daily for one day to one year, and may even be for thelife of the subject. Chronic, long-term administration may be indicated.

Combination Therapies

The compounds and pharmaceutical compositions of the present inventioncan be formulated and employed in combination therapies, that is, thecompounds and pharmaceutical compositions can be formulated with oradministered concurrently with, prior to, or subsequent to, one or moreother desired therapeutics or medical procedures. The particularcombination of therapies (therapeutics or procedures) to employ in acombination regimen will take into account compatibility of the desiredtherapeutics and/or procedures and the desired therapeutic effect to beachieved. It will also be appreciated that the therapies employed mayachieve a desired effect for the same disorder, or they may achievedifferent effects (e.g., control of any adverse effects).

Examples of other drugs to combine with the compounds described hereininclude pharmaceuticals for the treatment of malaria (e.g., chloroquine,quinine, pyrimethamine, sulfadoxine, mefloquine, artemether,lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine,proguanil, doxycycline, clindamycin, artemisinin, atovaquone, any othertherapeutic approved for the treatment of malaria, and any combinationthereof). Other examples of drugs to combine with the compoundsdescribed herein include pharmaceuticals for the treatment of different,yet associated or related symptoms or indications. Combination methodscan involve the use of the two (or more) agents formulated together orseparately, as determined to be appropriate by those of skill in theart. In one example, two or more drugs are formulated together for thesimultaneous or near simultaneous administration of the agents.

EXAMPLES

The following Examples illustrate the synthesis of a representativenumber of compounds and the use of these compounds in the treatment ofmalaria. Accordingly, the Examples are intended to illustrate but not tolimit the invention. Additional compounds not specifically exemplifiedmay be synthesized using conventional methods in combination with themethods described herein.

Example 1. Synthesis of Compounds Materials and Methods

Compounds of the present invention can be prepared beginning withcommercially available starting materials and utilizing generalsynthetic techniques and procedures known to those skilled in the art.Chemicals may be purchased from companies such as Aldrich, ArgonautTechnologies, VWR, and Lancaster. Chromatography supplies and equipmentmay be purchased from such companies as for example AnaLogix, Inc,Burlington, Wis.; Biotage AB, Charlottesville, Va.; Analytical Sales andServices, Inc., Pompton Plains, N.J.; Teledyne Isco, Lincoln, Nebr.; VWRInternational, Bridgeport, N.J.; Varian Inc., Palo Alto, Calif., andMultigram II Mettler Toledo Instrument Newark, Del. Biotage, ISCO andAnalogix columns are pre-packed silica gel columns used in standardchromatography.

Method A retention time method: UPLC-MS (Waters, Milford, Mass.). Mobilephase A consisted of either 0.1% ammonium hydroxide or 0.05% TFA inwater, while mobile phase B consisted of the same additives inacetonitrile. The gradient ran from 5% to 95% mobile phase B over 0.8min at 0.9 mL/min. An Acquity BEH C18, 1.7 μm, 2.1×50 mm column was usedwith column temperature maintained at 65° C.

Method B retention time method: UPLC-MS (Waters, Milford, Mass.). Mobilephase A consisted of either 0.1% ammonium hydroxide or 0.05% TFA inwater, while mobile phase B consisted of the same additives inacetonitrile. The gradient ran from 5% to 95% mobile phase B over 2.65min at 0.9 mL/min. An Acquity BEH C18, 1.7 μm, 2.1×50 mm column was usedwith column temperature maintained at 65° C.

The compounds of formula I can be prepared according to Schemes 1 to 15:

General synthetic scheme 1 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 1-4, 8, 10,11-15, 17-20, 22-25, 27-30, 34, 36, 38, 40, 44,45,49-52, 54, 56, 59, 60,63, 71, 72, 75, 78, 83, and 93:

General synthetic scheme 2 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 74:

General synthetic scheme 3 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 47:

General synthetic scheme 4 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 31:

General synthetic scheme 5 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 32, 33, and73:

General synthetic scheme 6 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 35, 80, 85,or 86

General synthetic scheme 7 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 34 and 79:

General synthetic scheme 8 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 37, 48, 55,57, and 84:

General synthetic scheme 9 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 39, 66, and77:

General synthetic scheme 10 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 5, 7, 9, 16,21, 26, 41, 42, 46, 64, 67, and 69:

General synthetic scheme 11 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 43 and 70:

General synthetic scheme 12 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 53:

General synthetic scheme 13 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 58, 65, 76,and 82:

General synthetic scheme 14 shows how compounds for certain embodimentsof the present invention can be prepared, such as compounds 61, 68, 88,and 92:

General synthetic scheme 15 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 62:

General synthetic scheme 16 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 81:

General synthetic scheme 17 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 87:

General synthetic scheme 18 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 89:

General synthetic scheme 19 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 90:

General synthetic scheme 20 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 91:

General synthetic scheme 21 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 94:

General synthetic scheme 22 shows how compounds for certain embodimentsof the present invention can be prepared, such as compound 95:

Synthesis of Compound 68

Loading of Lanterns

((8R,9R,10S)-9-(4-bromophenyl)-6-((2-nitrophenyl)sulfonyl)-1,6-diazabicyclo[6.2.0]decan-10-yl)methanolwas prepared using the procedure of Lowe and coworkers (J. Org. Chem.2012, 77, 7187-7211).

Solid-phase synthesis was conducted on silicon-functionalizedpolystyrene SynPhase Lanterns (L-series). 200 lanterns were dried undervacuum for 3 h then purged with nitrogen. Dichloromethane was added justto cover the lanterns, and 3% TfOH in DCM solution (40 mL) was added tothe lanterns. The vial was capped and shaken for 10 min. During theshaking the color changed to dark red. All the liquids were removedusing a syringe, and lutidine (3 mL) was added. The flask was sealed andshaken for a few minutes. A solution of((8R,9R,10S)-9-(4-bromophenyl)-6-((2-nitrophenyl)sulfonyl)-1,6-diazabicyclo[6.2.0]decan-10-yl)methanol(1837 mg, 3600 ρmol) in anhydrous DCM (120 mL) was quickly added to thelanterns. The reaction flask was shaken for 4 days. The solution wasremoved, and the lanterns were washed with DCM and dried.

Nosyl Deprotection

Lanterns were suspended in DMF (0.8 mL/lantern), and then thiophenol(0.033 ml, 0.320 mmol) was added, followed by potassium carbonate (0.066g, 0.480 mmol). The lanterns were shaken for 65 h at room temperature.Lanterns were filtered and washed with dichloromethane, THF,THF/isopropanol (3:1), THF/water (3:1), DMF, THF/water (3:1),THF/isopropanol (3:1) and THF.

Urea Capping

Dichloromethane (0.8 mL/lantern) was added to the lanterns, and1-isocyanato-4-methoxybenzene (20 equiv) was added. The lanterns wereshaken for 16 h at room temperature. Lanterns were filtered and washedwith dichloromethane, THF, THF/isopropanol (3:1), THF/water (3:1), DMF,THF/water (3:1), THF/isopronaol (3:1) and THF.

Sonogashira Reaction

The lanterns were placed in a vial, and DMF (0.8 mL/lantern) was addedto this vial. A cap with a rubber septum was placed on the vial, and thevial was evacuated and purged with argon. Pd(PPh₃)₄ (2.0 eq), CuI (3.0eq), ethynylbenzene (20 eq) and Et₃N (30 eq) were added to the vial. Thelanterns were placed in a shaker for 5 days at 35° C. Lanterns werewashed twice with DMF, THF/water (3:1), THF/isopropanol (3:1), and THF.A quarter lantern from each building block was cleaved by the proceduredescribed below and analyzed by HPLC. Lanterns were re-subjected to thereaction conditions once more if the unreacted starting material wasdetected.

Cleavage Protocol

Lanterns were taken in a vial, and 15% solution of HF/pyridine instabilized THF (350 μL/Lantern) was added. After 2 h the cleavagesolution was quenched with TMSOMe (700 μL/lantern). The samples wereconcentrated on a Genevac® solvent evaporation system overnight withoutheating. Purification was accomplished via SiO₂ chromatography to yield(8R,9R,10S)-10-(hydroxymethyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide(89% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.42 (m, 2H), 7.44-7.34 (m,4H), 7.31-7.24 (m, 3H), 7.17 (d, J=8.8 Hz, 2H), 6.75 (d, 8.82H), 6.05(s, 1H), 3.85-3.72 (m, 1H), 3.70 (s, 3H), 3.65-3.46 (m, 5H), 3.46-3.35(m, 1H), 3.30-3.15 (m, 1H), 3.01-2.90 (m, 1H), 2.86-2.74 (m, 1H),2.44-2.29 (m, 1H), 1.82-1.65 (m, 2H), 1.64-1.48 (m, 2H). MS (ESI) calcdfor C₃₁H₃₄N₃O₃ [M+H]+: 496.25 Found: 496.48.

In a flame dried flask under argon a solution of triphenylphosphine (772mg, 2.94 mmol) in THE (14.7 ml) at 0° C. was slowly added(E)-diisopropyl diazene-1,2-dicarboxylate (572 μl, 2.94 mmol). After 5min the mixture became milky yellow. Then 4.48 mL of the preparedmixture (DIAD+PPh₃+THF) (0.896 mmol) was added to the flask containing(8R,9R,10S)-10-(hydroxymethyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide(126 mg, 0.254 mmol) and phtalimide (56.1 mg, 0.381 mmol) in THE (500μL) at 0° C. The mixture was stirred for 2 h and was then concentratedand purified by silica chromatography to yield(8R,9R,10S)-10-(hydroxymethyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide(67% yield) which was used directly in the subsequent step.(8R,9S,10S)-10-((2,5-dioxopyrrolidin-1-yl)methyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamidewas dissolved in ethanol (1.85 ml), to this was added methylhydrazine(98 μl, 1.857 mmol), and the reaction mixture was stirred at 80° C.during 3 h. The reaction mixture was concentrated. Purification wasaccomplished via SiO₂ chromatography to yield(8R,9S,10S)-10-(aminomethyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6diazabicyclo[6.2.0]decane-6-carboxamide (46% yield). ¹H NMR (400 MHz,CDCl₃) δ 7.55-7.38 (m, 5H), 7.30-7.22 (m, 3H), 7.22-7.12 (m, 3H),6.81-6.64 (m, 2H), 6.05 (s, 1H), 3.84-3.73 (m, 1H), 3.69 (s, 3H),3.61-3.51 (m, 2H), 3.50-3.43 (m, 1H), 3.41-3.36 (m, 1H), 3.26-3.24 (m,2H), 2.97-2.85 (m, 1H), 2.85-2.76 (m, 1H), 2.76-2.68 (m, 1H), 2.33-2.23(m, 1H), 1.79-1.65 (m, 2H), 1.62-1.50 (m, 2H). MS (ESI) calcd forC₃₁H₃₅N₄O₂ [M+H]+: 495.27, Found: 495.49.

To(8R,9S,10S)-10-(aminomethyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide(150 mg, 0.303 mmol) in DCM (5 mL) under Ar was added magnesium sulfate(365 mg, 3.03 mmol) followed by formaldehyde (135 μl, 1.820 mmol).Anhydrous sodium triacetoxyhydroborate (900 mg, 4.25 mmol) was thenadded, and the reaction was stirred for 2 h. Sodium bicarbonate solutionwas then added, and the reaction was stirred for 15 minutes and thenextracted with DCM (3×). The reaction mixture was concentrated.Purification was accomplished via SiO₂ chromatography to yield(8R,9S,10S)-10-((dimethylamino)methyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide(73% yield)¹H NMR (300 MHz, CDCl₃) δ 7.59-7.42 (m, 5H), 7.41-7.32 (m,3H), 7.30-7.22 (m, 3H), 6.91-6.77 (m, 2H), 6.13 (s, 1H), 3.94-3.82 (m,1H), 3.79 (s, 3H), 3.71-3.43 (m, 4H), 3.31-3.16 (m, 1H), 3.12-2.99 (m,1H), 2.95-2.80 (m, 1H), 2.56-2.43 (m, 2H), 2.40-2.27 (m, 1H), 2.08 (s,6H), 1.91-1.71 (m, 3H), 1.72-1.55 (m, 1H). MS (ESI) calcd for C₃₃H₃₉N₄O₂[M+H]+: 523.299, Found: 523.63.

Example 2. Activity of Selected Compounds Against the Dd2 Strain of P.falciparum

The Dd2 strain of P. falciparum was cultured in complete medium (RPMIwith L-glutamine, 4.3% heat-inactivated 0-positive human serum, 2.08mg/ml albumax, 0.013 mg/ml hypoxanthine, 1.17 mg/ml glucose, 0.18%NaHCO₃, 0.031 M Hepes, 2.60 mM NaOH, and 0.043 mg/ml gentamicin) untilthe parasitemia reached 3-8%. Parasitemia was determined by checking atleast 500 red blood cells from a Giemsa-stained blood smear. The Dd2cultures along with tested 0-positive red blood cells were centrifugedat room temperature at 2,000 rpm for 5 minutes using an Eppendorfcentrifuge 5810R with an A-4-81 rotor. The medium was aspirated off. Forthe compound screening, a parasite dilution at a 1% parasitemia and 1.0%hematocrit was created with screening medium (RPMI with L-glutamine,4.16 mg/ml albumax II, 0.013 mg/ml hypoxanthine, 1.73 mg/ml glucose,0.18% NaHC₃, 0.031 M Hepes, 2.60 mM NaOH, and 0.043 mg/ml gentamicin).The suspension was gassed with 93% nitrogen, 4% carbon dioxide, and 3%oxygen and placed at 37° C. until needed. Using a liquid dispenser, 20μl of screening medium was dispensed into 384-well, black, clear-bottomplates. With a PinTool, 100 nl of compounds dissolved in DMSO wastransferred into the assay plates along with control compound(mefloquine). Next, 30 μl of the parasite suspension in screening mediumwas then dispensed into the assay plates such that the final parasitemiawas 1% and the final hematocrit was 1.0%. Final concentration of DMSOwas 0.125%. Mefloquine at a final concentration of 20 μM and DMSO at afinal concentration of 0.125% were used within the assay plates to serveas background and baseline controls, respectively. The assay plates weretransferred to incubators (93% nitrogen, 4% carbon dioxide, and 3%oxygen during the 72 h incubation at 37° C.). Ten microliters ofdetection reagent consisting of 10×SYBR Green I (Invitrogen; supplied in10,000× concentration) in lysis buffer (20 mM Tris-HCl, 5 mM EDTA, 0.16%Saponin wt/vol, 1.6% Triton X vol/vol) was dispensed into the assayplates. For optimal staining, the assay plates were left at roomtemperature for 24 h in the dark. The assay plates were read by using anEnvision (PerkinElmer) reader, with 505 dichroic mirrors with 485-nmexcitation and 530-nm emission settings, and the plate reads were fromthe bottom.

By following the above-described protocol, the 50% effectiveconcentration (EC₅₀) for compounds 1-95 was measured against P.falciparum Dd2 and the results are shown in Table 2: Table 2

TABLE 2 Compound EC₅₀ Dd2 Number (nM) 1 427 2 165 3 118 4 131 5 1066 6552 7 1194 8 83 9 518 10 949 11 17 12 950 13 44 14 1196 15 254 16 618 17560 18 800 19 805 20 1326 21 623 22 507 23 386 24 418 25 155 26 955 27 428 368 29 898 30 42 31 1824 32 158 33 2324 34 4659 35 65 36 7900 37 14838 15 39 5170 40 5160 41 9830 42 9680 43 229 44 1097 45 846 46 17828 4723 48 36 49 65 50 1234 51 11 52 17 53 2771 54 156 55 5 56 80 57 98 58 659 2700 60 61 61 47 62 4430 63 1229 64 1010 65 110 66 1313 67 19500 68 369 19500 70 13 71 34 72 17 73 104 74 87 75 71 76 8 77 4886 78 61 79 85080 23 81 34 82 3 83 24 84 52 85 0.4 86 2 87 1 88 25 89 8 90 228 91 14 92108 93 138 94 14 95 5000

Example 3. In Vivo PK/Efficacy of Selected Compounds

In vivo antimalarial activity for certain compounds of the invention wasassessed for groups of three-five female NMRI mice (20-22 mg)intravenously infected on day 0 with P. berghei strain ANKA (2×10⁷parasitized erythrocytes per ml). In control mice, parasitemia typicallyrose to ˜40% by day 3 after infection, and control mice died between day5 and day 7 after infection. Compounds with a dosage of 50 mg/kg wereformulated in 7% Tween80/3% ethanol and were administered orally asthree consecutive daily doses (24, 48, and 72 h after infection). Theblood smears were collected and stained on day 4 after infection. Thedegree of infection (parasitemia expressed as percent infectederythrocytes) was determined microscopically, with a detection limit of1 parasite in 10,000 erythrocytes (that is, 0.01%). Activity wascalculated as the difference between the mean percent parasitemia forthe control and treated groups expressed as a percent relative to thecontrol group. Using this method, a compound of the invention(8R,9R,10S)-10-(hydroxymethyl)-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide(compound 27) reduced parasitaemia by 57% on day 4. For pharmacokineticsanalyses, blood samples were collected at 1, 4, and 24 hours afterdosing and were immediately centrifuged and the plasma separated andfrozen at −20° C. Before analysis by LC/MS, plasma proteins wereprecipitated by the addition of acetonitrile (2:1 v/v). Quantificationwas conducted by comparison to a calibration curve prepared using blankplasma and processed in the same way as the samples.

Example 4. Single Dose In Vivo Efficacy of Selected Compounds

CD-1 mice (female, 6-7-week-old) were inoculated with 1×10⁶ P. berghei(ANKA GFP-luc) blood stage parasites intravenously 24 hours beforetreatment and compounds were administered as a single 100 or 50 mg/kgdose orally at 0 hour. Parasitemia was monitored by the In vivo ImagingSystem (IVIS 100, Xenogen; Caliper Life Science) to acquire thebioluminescence signal. Animals with parasitemia exceeding 25% wereeuthanized.

The results are shown in FIG. 1 (Panels A and B). Infection proceedsrapidly in untreated mice (control), which were euthanized around day 6of the study. Compound 37 and 68 were tested at different times; thusthe artesunate control (ART) is shown for each compound. A single 100mg/kg dose of ART results in rapid suppression of parasites, but, due toits short half-life, the parasites re-emerge quickly. A single 100 mg/kgdose of compound 37 repressed parasitemia for about 1 week (ED₂₅=100mg/kg in this study), while a single 50 mg/kg dose of compound 68resulted in 100% cure of the infected animals (ED₁₀₀≤50 mg/kg). Allimages are normalized to the same color scale.

Example 5. Prevention of Transmission of P. berghei to Mosquitoes

CD-1 mice were infected with P. berghei (ANKA GFP-luc) for 96 hoursprior to treatment with vehicle [70% PEG400 and 30% (5% glucose in H₂O)]or single ascending doses of compound 37 (Day 0). Average % parasitemiaon Day 0 was 2.1%. On Day 2 of the study, mice were anesthetized andfemale Anopheles stephensi mosquitoes were allowed to feed on the micefor 20 minutes. On Day 9, the midguts of the mosquitoes were dissectedout, and oocysts were enumerated microscopically (12.5× magnification,oocysts visible as puncta in the control, FIG. 2, Panel A).

Mosquitoes fed on untreated mice had many visible oocysts (210.4±30.6),while mosquitoes fed on compound 37 animals (all doses) had nodetectable oocysts (FIG. 2, Panel B).

Example 6. In Vivo P. berghei Liver Stage Assay

CD-1 mice were inoculated (IV) with 1×105 P. berghei (ANKA luc-GFP)sporozoites freshly dissected out from A. stephensi and immediatelytreated with a single dose (PO) of vehicle or compound 37 (25, 5.0, 1.0or 0.2 mg/kg) at 0 hour. Bioluminescence signals from the transgenicparasites were monitored by the In vivo Imaging System (IVIS 100,Xenogen; Caliper Life Science).

Untreated control animals showed systemic (blood stage) parasitemia byday 3, while atovaquone (ATV) and compound 37-treated animals (dosed at≥5 mg/kg) remained parasite free (FIG. 3), demonstrating effectiveinhibition of liver stage parasites. The ED₅₀ for compound 37 in thisassay was 1 mg/kg.

OTHER EMBODIMENTS

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure come within known or customary practice within theart to which the invention pertains and may be applied to the essentialfeatures hereinbefore set forth.

The invention is further described in the following numbered paragraphs.

1. A compound according to formula (I):

wherein the dotted line represents an optional double bond;

m is 0 or 1;

n is 0, 1, or 2;

A is CH or N;

X is absent or —C≡C—;

R¹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Y is C₁-C₆ alkylene, —C(O)NR⁴—; —SO₂—, or —C(O)—;

R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryl C₁-C₆ alkyl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;

R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl;

R⁴ is hydrogen or C₁-C₆ alkyl;

R⁵ and R⁶ are independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ acyl; and

R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉ heterocyclyl;

wherein said compound does not have the structure of any one ofcompounds 1 to 30 of Table 1;

or a pharmaceutically acceptable salt thereof.

2. The compound of paragraph 1, wherein said compound has the structure:

3. The compound of paragraph 1, wherein said compound has the structure:

4. The compound of any one of paragraphs 1 to 3, wherein X is —C≡C—.

5. The compound of any one of paragraphs 1 to 4, wherein R¹ is C₆-C₁₀aryl.

6. The compound of any one of paragraphs 1 to 5, wherein Y is —C(O)NR⁴—.

7. The compound of any one of paragraphs 1 to 6, wherein R² is C₆-C₁₀aryl, C₃-C₁₀ carbocyclyl, or C₂-C₉ heteroaryl.

8. The compound of any one of paragraph 1, wherein said compound has thestructure:

wherein o and p are independently 1, 2, 3, 4, or 5; and

R⁸ and R⁹ are independently hydrogen, halogen, or C₁-C₆ heteroalkyl.

9. The compound of any one of paragraphs 1 to 8, wherein —ZR³ ishydrogen or —CO₂H.

10. The compound of any one of paragraphs 1 to 8, wherein Z ismethylene.

11. The compound of any one of paragraphs 1, 2, 8, or 10, wherein R³ ishydroxyl, 4-methylpiperazyl, 4-hydroxy-4-methyl-piperidyl,3-hydroxyl-3-methyl-azetidinyl, —OCH₂C(O)OH, —NH₂, morpholinyl,—NHC(O)CH₃, —NHCH₃, —N(CH₃)₂, or —N(CH₃)C(O)CH₃.

12. The compound of any one of paragraphs 1 to 8 or 11, wherein Z is—CH₂OCH₂— or —CH₂OCH₂CH₂.

13. The compound of any one of paragraphs 1 to 8, 10, or 12, wherein R³is C(O)R⁷.

14. The compound of paragraph 13, wherein R⁷ is hydroxyl, methoxy, ormorpholino.

15. The compound of any one of paragraphs 1 to 5, or 9 to 14, wherein—YR² is —CH₂CH₂CF₃.

16. The compound of any one of paragraphs 1 to 5, 7, or 9 to 14, whereinY is methylene or —SO₂—.

17. The compound of any one of paragraphs 1 to 14 or 16, wherein R² is4-methoxy-phenyl.

18. The compound of any one of paragraphs 1 to 4, 6, 7, or 9 to 17,wherein R¹ is C₂-C₉ heteroaryl.

19. The compound of paragraph 18, wherein said C₂-C₉ heteroaryl is2-pyridyl or 3-pyridyl.

20. The compound of paragraph 18 or 19, wherein Y is —C(O)NH—.

21. The compound of paragraph 20, wherein R² is C₆-C₁₀ aryl.

22. The compound of any one of paragraphs 1 to 8, or 15 to 21, wherein—ZR₃ is hydrogen, —CH₂OH, —CH₂NH₂, or —CH₂NHC(O)CH₃.

23. The compound of paragraph 18 or 19, wherein Y is methylene.

24. The compound of any one of paragraphs 1 to 14, 16, or 18 to 22,wherein R² is 3-methoxy-phenyl.

25. The compound of any one of paragraphs 1 to 4, 5 to 7, 9 to 17, or 20to 24, wherein R is iso-butyl, —CH₂OCH₃, cyclopropyl, cyclopentyl, orcyclohexyl.

26. The compound of paragraph 25, wherein Y is —C(O)NH—.

27. The compound of paragraph 26, wherein R² is 2-methoxy-phenyl or4-methoxy-phenyl.

28. The compound of paragraph 25, wherein Y is —SO₂—.

29. The compound of any one of paragraphs 1 to 6, 9 to 14, 16, 18 to 20,22, 23, 25, 26, or

28, wherein R² is 4-methoxy-phenyl or benzyl.

30. The compound of any one of paragraphs 1 to 3, 5 to 7, or 9 to 29,wherein X is absent.

31. The compound of paragraph 30, wherein R¹ is hydrogen, phenyl,2-fluoro-phenyl, 3-fluorophenyl, 4-fluoro-phenyl, 3-methyl-phenyl,4-methyl-phenyl, cyclohexenyl, 2-phenyl-1,3-thiazol-4-yl,1-phenyl-pyrrol-3-yl, 4-pyridyl, or 1-phenyl-1H-pyrazol-3-yl.

32. The compound of paragraph 30 or 31, wherein —ZR³ is —CH₂OH.

33. The compound of any one of paragraphs 30 to 32, wherein —YR² is—CH₂CH₂CF₃.

34. The compound of any one of paragraphs 30 to 32, wherein Y is —SO₂—and R² is 3-methyl-phenyl or 4-fluoro-phenyl.

35. The compound of any one of paragraphs 30 to 32, wherein Y is—C(O)NH— and R² is 4-methoxy-phenyl.

36. The compound of any one of paragraphs 1 to 35, wherein A is CH.

37. The compound of any one of paragraphs 1 to 35, wherein A is N.

38. A compound having the structure of any one of compounds 31 to 95 ofTable 1 or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound having the structure:

wherein the dotted line represents an optional double bond;

m is 0 or 1;

n is 0, 1, or 2;

A is CH or N;

X is absent or —C≡C—;

R¹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Y is C₁-C₆ alkylene, —C(O)NR⁴—; —SO₂—, or —C(O)—;

R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryl C₁-C₆ alkyl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;

R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl;

R⁴ is hydrogen or C₁-C₆ alkyl;

R⁵ and R⁶ are independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ acyl; and

R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉ heterocyclyl;

or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable excipient.

40. The pharmaceutical composition of paragraph 39, wherein saidcompound has the structure of any one of compounds 1 to 95 of Table 1 ora pharmaceutically acceptable salt thereof.

41. The pharmaceutical composition of paragraph 39, wherein saidcompound has the structure of any one of paragraphs 2 to 37.

42. A method of preventing or treating malaria in a subject, comprisingthe step of administering to the subject an effective amount of acompound having the structure:

wherein the dotted line represents an optional double bond;

m is 0 or 1;

n is 0, 1, or 2;

A is CH or N;

X is absent or —C≡C—;

R¹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Y is C₁-C₆ alkylene, —C(O)NR⁴—; —SO₂—, or —C(O)—;

R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryl C₁-C₆ alkyl, C₃-C₁₀carbocyclyl, or C₂-C₉ heteroaryl;

Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;

R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl;

R⁴ is hydrogen or C₁-C₆ alkyl;

R⁵ and R⁶ are independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ acyl; and

R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉ heterocyclyl;

or a pharmaceutically acceptable salt thereof.

43. The method of paragraph 42, wherein said compound has the structureof any one of compounds 1 to 95 of Table 1 or a pharmaceuticallyacceptable salt thereof.

44. The method of paragraph 42 or 43, wherein said malaria is drugresistant malaria.

45. The method of paragraph 44, wherein drug resistant malaria isresistant to chloroquine, quinine, prymethamine, sulfadoxine,mefloquine, artemether, lumefantrine, artesunate, amodiaquine,dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin,artemisinin, atovaquone, or any combination thereof.

46. The method of any one of paragraphs 42 to 45, wherein said malariais liver stage malaria.

47. The method of any one of paragraphs 42 to 46, wherein the liver ofsaid subject is infected with a malaria-causing parasite and saidtreatment prevents spread of said infection from their liver.

48. The method of any one of paragraphs 42 to 45, wherein said malariais blood stage malaria.

49. The method of any one of paragraphs 42 to 45, wherein said malariais transmission stage malaria.

50. The method of any one of paragraphs 42 or 44 to 49, wherein saidcompound has the structure of any one of paragraphs 2 to 37.

1. A compound according to formula (I):

wherein the dotted line represents an optional double bond; m is 0 or 1;n is 0, 1, or 2; A is CH or N; X is absent or —C≡C—; R¹ is hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, or C₂-C₉ heteroaryl; Y isC₁-C₆ alkylene; R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ arylC₁-C₆ alkyl, C₃-C₁₀ carbocyclyl, or C₂-C₉ heteroaryl, wherein R² is not2-methoxyphenyl; Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl; R⁴ ishydrogen or C₁-C₆ alkyl; R⁵ and R⁶ are independently hydrogen, C₁-C₆alkyl, or C₁-C₆ acyl; and R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉heterocyclyl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, wherein said compound has the structure:


3. The compound of claim 1, wherein said compound has the structure:


4. The compound of claim 1, wherein X is —C≡C—.
 5. The compound of claim1, wherein R¹ is C₆-C₁₀ aryl.
 6. (canceled)
 7. The compound of claim 1,wherein R² is C₆-C₁₀. 8-9. (canceled)
 10. The compound of claim 1,wherein Z is methylene.
 11. The compound of claim 1, wherein R³ ishydroxyl, 4-methylpiperazyl, 4-hydroxy-4-methyl-piperidyl,3-hydroxyl-3-methyl-azetidinyl, —OCH₂C(O)OH, —NH₂, morpholinyl,—NHC(O)CH₃, —NHCH₃, —N(CH₃)₂, or —N(CH₃)C(O)CH₃. 12-15. (canceled) 16.The compound claim 1, wherein Y is methylene.
 17. The compound of claim1, wherein R² is substituted phenyl. 18-38. (canceled)
 39. Apharmaceutical composition comprising a therapeutically effective amountof a compound having the structure:

wherein the dotted line represents an optional double bond; m is 0 or 1;n is 0, 1, or 2; A is CH or N; X is absent or —C≡C—; R¹ is hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, or C₂-C₉ heteroaryl; Y isC₁-C₆ alkylene; R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ arylC₁-C₆ alkyl, C₃-C₁₀ carbocyclyl, or C₂-C₉ heteroaryl, wherein R² is not2-methoxyphenyl; Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl; R⁴ ishydrogen or C₁-C₆ alkyl; R⁵ and R⁶ are independently hydrogen, C₁-C₆alkyl, or C₁-C₆ acyl; and R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉heterocyclyl; or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable excipient. 40-41. (canceled)
 42. A method ofpreventing or treating malaria in a subject, comprising the step ofadministering to the subject an effective amount of a compound havingthe structure:

wherein the dotted line represents an optional double bond; m is 0 or 1;n is 0, 1, or 2; A is CH or N; X is absent or —C≡C—; R¹ is hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₆-C₁₀ aryl, or C₂-C₉ heteroaryl; Y isC₁-C₆ alkylene; R² is C₁-C₆ perfluoroalkyl, C₆-C₁₀ aryl, C₆-C₁₀ arylC₁-C₆ alkyl, C₃-C₁₀ carbocyclyl, or C₂-C₉ heteroaryl, wherein R² is not2-methoxyphenyl; Z is absent, C₁-C₆ alkylene, or C₁-C₆ heteroalkylene;R³ is hydrogen, hydroxyl, —NR⁵R⁶, —C(O)R⁷, or C₂-C₉ heterocyclyl; R⁴ ishydrogen or C₁-C₆ alkyl; R⁵ and R⁶ are independently hydrogen, C₁-C₆alkyl, or C₁-C₆ acyl; and R⁷ is hydroxyl, C₁-C₆ heteroalkyl, or C₂-C₉heterocyclyl; or a pharmaceutically acceptable salt thereof. 43.(canceled)
 44. The method of claim 42, wherein said malaria is drugresistant malaria.
 45. The method of claim 44, wherein drug resistantmalaria is resistant to chloroquine, quinine, prymethamine, sulfadoxine,mefloquine, artemether, lumefantrine, artesunate, amodiaquine,dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin,artemisinin, atovaquone, or any combination thereof.
 46. The method ofclaim 42, wherein said malaria is liver stage malaria, blood stagemalaria, or transmission stage malaria.
 47. The method of claim 42,wherein the liver of said subject is infected with a malaria-causingparasite and said treatment prevents spread of said infection from theirliver. 48-49. (canceled)
 50. The compound according to claim 1, whereinR² is phenyl substituted with —CH₃, —OCH₃ or halogen.
 51. The compoundaccording to claim 1, wherein R² is phenyl substituted with halogen. 52.The compound according to claim 1, wherein R² is not 3-methoxyphenyl or4-methoxyphenyl.
 53. The compound according to claim 1, wherein R¹ issubstituted phenyl.